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Research Interests: Dr. Oberdick's lab studies the development and function of the cerebellum using genetically manipulated mouse models.

Current Research: Dr. Oberdick's lab is interested in understanding the development and function of the cerebellum, both in its own right as a key brain center for sensorimotor control, and as a simple and well-studied model for understanding the brain as a whole. The main approach is using genetically modified mouse models. There are four main projects:

Mechanisms and function of mRNA trafficking in Purkinje cell dendrites

Mechanisms underlying cerebellar zone formation

Physiological and behavioral analysis of the signal-tuning properties of the GoLoco protein, L7/Pcp2. The goal of the latter project is to unravel a novel gating mechanism of the cerebellum that affects dynamic aspects of cerebellar-mediated sensorimotor learning, as well as emotional and other non-motor behaviors.

The Sensorimotor Damper and Control of Emotional Behaviors By the Cerebellum
In published mouse studies Dr. Oberdick's team has shown that loss of the Purkinje cell-specific GoLoco protein, L7/Pcp2, leads to enhancement of motor learning on the rotarod over several days of training (Iscru et al., 2009). Rather than a motor learning effect per se, this may be due to enhanced motivation since male mutants also show decreased despair (less depressive-like behavior) on the forced swim test (Walton et al., 2012).

In addition, this research has shown sex dimorphic effects of L7/Pcp2 inactivation on exploration in an open-field and during acquisition of tone-cued fear conditioning: reduced anxiety and fear responses to stimuli in male mutants and the opposite effect in females (Walton et al., 2012).

Extrapolating based on an earlier in vitro study researchers believe that L7/Pcp2 can act bidirectionally depending upon the specific physiological and/or hormonal milieu — which may be presumed to vary regionally within the cerebellum. In this earlier study, they showed a dose-dependent and bidirectional modulatory effect of L7/Pcp2 on inhibition of the P/Q-type Ca2+ channel by Gi/o-protein coupled receptors, enhancing Gi/oPCR-dependent channel inhibition at low [L7] and decreasing it at high [L7] (Kinoshita-Kawada et al., 2004). Thus, L7/Pcp2 adjusts or tunes the dynamic range of Gi/oPCR responses, acting to essentially decouple such receptors at high [L7]. Dr. Oberdick's team believes this biochemical property of L7/Pcp2 is a central component of a mood stabilizing function of the cerebellum.

Engrailed-2 and the Development of Cerebellar Zones
The gene Engrailed-2 (En-2) has been associated with autism in multiple studies. There is a great deal of interest in understanding the specific roles of this gene at various stages of development both in midbrain dopaminergic neurons and in the cerebellum. Inactivation of En-2 by Alexandra Joyner and colleagues has revealed an effect on the early genesis of cerebellar cells and subtle effects on the formation of zones.

Researchers have taken the complementary gain-of-function (gof) approach by using the L7 promoter to overexpress En-2 selectively in cerebellar Purkinje cells starting from late embryogenesis, a time frame when En-2 normally is only weakly expressed in well-isolated subsets of these cells. This has a similar effect on cerebellar size as En-2 gene inactivation, except that the gof effect is due to an early postnatal degeneration of selected Purkinje cells and secondary loss of associated neurons rather than an effect on cell generation.

In addition and in spite of the loss of about 50 percent of cerebellar cells, the fundamental organization of cerebellar zones is intact as revealed by a truncated L7-lacZ transgene — a so-called “early onset” marker of cerebellar zones (see figure, left side). On the other hand, not all molecular markers of zones reveal the same integrity of expression in the wake of En-2 gof and as shown in the figure (right side), zebrinII — a classic “late onset” marker of zones— reveals relatively diffuse and more uniform expression.

In addition — in collaboration with Michael Vogel — Dr. Oberdick's lab showed that the distribution of mossy fibers was less organized than normal (Baader et al., 1999). The status of climbing fibers in these transgenics remains unknown, but the lab's prediction is that their organization would remain relatively unscathed. Regardless, observations indicate the importance of neonatal downregulation of En-2 in Purkinje cells during normal development.

Further studies with the team's collaborator, Stephan Baader, indicate that restricted and zonal expression of En-2 during the first postnatal week may normally play a role in natural cell death. Studies also indicate that this process and/or others regulated by En-2 may be an integral part of sculpting the precise pattern of mossy fiber and late-onset molecular banding patterns (Jankowski et al., 2011).

Selective disruption of “late onset” sagittal banding patterns in the cerebellum by ectopic expression of Engrailed 2 in Purkinje cells. Ectopic overexpression of En2 during the perinatal period results in decreased cerebellar size due to partial Purkinje cell loss, but no major effect on adult early onset banding patterns such as L7-lacZ, a zone reporter with a truncated L7 promoter (left). The integrity of zones in lobule VIII is particularly prominent. In contrast, late onset zone patterns such as zebrinII are grossly perturbed in L7-En2 mice particularly in lobule VIII, shown in a lobule reconstruction (right). All images are from 3-month-old animals. Data from Baader et al. (1999) J. Neurosci. 19, 5370-5379.

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